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Background: REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown.Methods: We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-COV-2 infection (as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity).Results: Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted.Conclusions: Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.). [ABSTRACT FROM AUTHOR]

Objective: To develop and apply a model to assess the economic value of a workplace influenza programme from the perspective of the employer. Design: The model calculated the avoided costs of influenza, including treatment costs, lost productivity, lost worker added value and the cost of replacing workers. Subtracted from this benefit were the costs associated with a vaccination programme, including administrative costs, the time to give the vaccine, and lost productivity due to adverse reactions. The framework of the model can be applied to any company to estimate the cost-benefit of an influenza immunisation programme. Setting: The model developed was applied to 4030 workers in the core divisions of a Brazilian pharma-chemical company. Results: The model determined a net benefit of $US121 441 [129 335 Brazilian reals ($Brz)], or $US35.45 ($Brz37.75) per vaccinated employee (1997 values). The cost-benefit ratio was 1 : 2.47. The calculations were subjected to a battery of 1-way and 2-way sensitivity analyses that determined that net benefit would be retained as long as the vaccine cost remained below $US45.40 ($Brz48.40) or the vaccine was at least 32.5% effective. Other alterations would retain a net benefit as well, including several combinations of incidence rate and vaccine effectiveness. Conclusions: The analysis suggests that providing an influenza vaccination programme can incur a substantial net benefit for an employer, although the size of the benefit will depend upon who normally absorbs the costs of treating influenza and compensating workers for lost work time due to illness, as well as the type of company in which the immunisation programme is applied. [ABSTRACT FROM AUTHOR]

Focuses on the safety of simultaneous pneumococcal and influenza vaccination in elderly patients in Brazil. Number of the elderly population in Brazil; Association between the risk of mobility and mortality and the respiratory infections of the elderly; Recommendation by the World Health Organization to administer pneumococcal and influenza vaccination to the elderly in Brazil.

A influenza (gripe) é doença infecciosa aguda de origem viral que acomete o trato respiratório e a cada inverno atinge mais de 100 milhões de pessoas na Europa, Japão e Estados Unidos, causando anualmente a morte de cerca de 20 a 40 mil pessoas somente neste último país. O agente etiológico é o Myxovirus influenzae, ou vírus da gripe. Este subdivide-se nos tipos A, B e C, sendo que apenas os do tipo A e B apresentam relevância clínica em humanos. O vírus influenza apresenta altas taxas de mutação, o que resulta freqüentemente na inserção de novas variantes virais na comunidade, para as quais a população não apresenta imunidade. São poucas as opções disponíveis para o controle da influenza. Dentre essas, a vacinação constitui a forma mais eficaz para o controle da doença e de suas complicações. Em função das mutações que ocorrem naturalmente no vírus influenza, recomenda-se que a vacinação seja realizada anualmente. No Brasil, segundo dados obtidos pelo Projeto VigiGripe - ligado à Universidade Federal de São Paulo -, verifica-se que a influenza apresenta pico de atividade entre os meses de maio e setembro. Assim, a época mais indicada para a vacinação corresponde aos meses de março e abril. Para o tratamento específico da influenza estão disponíveis quatro medicamentos antivirais: os fármacos clássicos amantadina e rimantidina e os antivirais de segunda geração oseltamivir e zanamivir. Os últimos, acrescentam alternativas para o tratamento da influenza e ampliam as opções disponíveis para o seu controle.

Increased use of antiviral monoclonal antibodies (mAbs) for treatment and prophylaxis necessitates better understanding of their impact on endogenous immunity to vaccines and viruses. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presented an opportunity to study immunity in individuals who received antiviral mAbs and were subsequently immunized with vaccines encoding the mAb-targeted viral spike antigen. Here, we describe the impact of administration of an antibody combination, casirivimab plus imdevimab (CAS+IMD), on immune responses to subsequent SARS-CoV-2 vaccination in humans, nonhuman primates, and mice. The presence of CAS+IMD at the time of vaccination led to a specific diminishment of vaccine-elicited pseudovirus neutralizing antibody titers without overall dampening of spike protein-directed immune responses, including antibody, B cell, and T cell responses. The impact on pseudovirus neutralizing titers extended to other therapeutic anti-spike protein antibodies when used as either monotherapy or combination therapy. The specific reduction in pseudovirus neutralizing titers was the result of epitope masking, a phenomenon where specific epitopes are bound by high-affinity antibodies and blocked from B cell recognition. Encouragingly, this reduction in pseudovirus neutralizing titers was reversible with additional booster vaccination. Moreover, by assessing the antiviral immune response in SARS-CoV-2-infected individuals treated therapeutically with CAS+IMD, we demonstrated alteration of antiviral humoral immunity in those who had received mAb therapy, but only in those individuals who had yet to start mounting their natural immune response at the time of mAb treatment. Together, these data demonstrate that antiviral mAbs can alter endogenous humoral immunity during vaccination or infection.

Background: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes., Methods: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and ≥65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete., Findings: Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group., Interpretation: Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases., Funding: Regeneron Pharmaceuticals and F Hoffmann-La Roche., Competing Interests: Declaration of interests FI and JDH are employees and stockholders of Regeneron Pharmaceuticals, and report having patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. AMGO, BAO, TB, SG, LF, SCI, MT, GPG, and BM are employees and stockholders of Regeneron Pharmaceuticals. JM is an employee of Regeneron Pharmaceuticals. EF-N is a former employee and current stockholder of Regeneron Pharmaceuticals, and reports patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. IH is an employee and stockholder of Regeneron Pharmaceuticals, and a stockholder of Merck & Co. ATH is an employee and stockholder of Regeneron Pharmaceuticals, is a stockholder of Pfizer, and reports a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals. AB, CAK, and GDY are employees and stockholders of Regeneron Pharmaceuticals and report having issued patents (US patent numbers 10 787 501, 10 954 289, and 10 975 139) and pending patents, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. CDP is an employee and stockholder of Regeneron Pharmaceuticals and reports a patent pending with Regeneron Pharmaceuticals. MJM reports funding from Regeneron Pharmaceuticals, paid to her institution, and grants from the US National Institute of Allergy and Infectious Diseases, the Biomedical Advanced Research and Development Authority, Moderna, Sanofi Pasteur, and Janssen, paid to her institution. SCDR reports grants from the National Institutes of Health and the Bill & Melinda Gates Foundation awarded to his institution, and contracts from Regeneron Pharmaceuticals, The Henry M Jackson Foundation, Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals), Gates Medical Research Institute, Paul G Allen Family Foundation, and Battelle, awarded to his institution. KWC reports funding from Regeneron Pharmaceuticals, paid to her institution, and is an employee and stockholder of Moderna. LDW CAH, AJO, AHP, and GDT report funding and provision of study materials from Regeneron Pharmaceuticals, paid to their institution. GAH is an employee and stockholder of Regeneron Pharmaceuticals and reports having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application. MM, JH, LP, and FAF declare no competing interests., (Copyright © 2024. Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Virologic determinants of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were defined in a post hoc analysis of prospectively studied vaccine- and infection-naïve individuals at high risk for coronavirus disease 2019 (COVID-19)., Methods: This phase 3 COVID-19 prevention trial (NCT04452318) with casirivimab and imdevimab was conducted in July 2020-February 2021, before widespread vaccine availability. Placebo-treated participants who were uninfected (SARS-CoV-2 quantitative reverse transcription polymerase chain reaction [RT-qPCR] negative) and seronegative were assessed weekly for 28 days (efficacy assessment period [EAP]) for COVID-19 symptoms and SARS-CoV-2 infection by RT-qPCR of nasopharyngeal swab samples and for serostatus by antinucleocapsid immunoglobulin (Ig) G. Regression-based modeling, including causal mediation analysis, estimated the effects of viral load on seroconversion., Results: Of 157/1069 (14.7%) uninfected and seronegative (for antispike IgG, antispike IgA, and antinucleocapsid IgG) participants who became infected during the EAP, 105 (65%) seroconverted. The mean (SD) maximum viral load of seroconverters was 7.23 (1.68) log 10 copies/mL vs 4.8 (2.2) log 10 copies/mL in those who remained seronegative; viral loads of ∼6.0   log 10 copies/mL better predicted seroconversion. The mean of the maximum viral load was 7.11 log 10  copies/mL in symptomatic participants vs 5.58 log 10  copies/mL in asymptomatic participants. The mean duration of detectable viral load was longer in seroconverted vs seronegative participants: 3.24 vs 1.63 weeks., Conclusions: Maximum SARS-CoV-2 viral load is a major driver of seroconversion and symptomatic COVID-19, with high viral loads (∼6.0 log 10  copies/mL) better predicting seroconversion. Serology underestimates infection rates, incidence, and prevalence of SARS-CoV-2 infection., Competing Interests: Potential conflicts of interest. M.X., K.-C.C., B.H., and B.J.M. are Regeneron Pharmaceuticals, Inc., employees/shareholders and report grants from BARDA. M.P.O. and G.A.H. are Regeneron Pharmaceuticals, Inc., employees/stockholders who report having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., as well as a pending patent application, and report grants from BARDA. A.T.H. is a Regeneron Pharmaceuticals, Inc., employee/stockholder and a Pfizer stockholder and has a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., and reports grants from BARDA. E.F.-N. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals, Inc., and reports having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., as well as a pending patent application, and reports grants from BARDA. F.I. and J.D.H. are Regeneron Pharmaceuticals, Inc., employees/stockholders who report having a patent pending, which has been licensed and for which they are receiving royalties, with Regeneron Pharmaceuticals, Inc., and report grants from BARDA. P.H. is a former Regeneron Pharmaceuticals, Inc., employee and current stockholder and reports grants from BARDA. M.A.M. reports being an employee of the federal government, which, as part of USG, through Operation Warp Speed, supported the clinical trial network involved in implementation of this effort. M.S.C. reports a relationship with the National Institutes for Health for study funding and Regeneron Pharmaceuticals, Inc., for drug studies; reports receiving consulting fees from Aerium for a Scientific Advisory Board and Atrea for a Medical Advisory Board; reports receiving payment for lectures from NY Course, MJH Life Sciences, Clinical Care Solutions, Virology Education, Amgen, Medscape, and UpToDate; reports receiving payment for an educational panel from AstraZeneca and GSK; reports receiving support for attending meetings with Krog Healthcare-GSK and Trinity Health Sciences; and has a leadership role for the HIV Prevention Trials Network, COVID-19 Prevention Network., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 ., (© 2023. The Author(s).)

While new vaccines for SARS-CoV-2 are authorized based on neutralizing antibody (nAb) titer against emerging variants of concern, an analogous pathway does not exist for preventative monoclonal antibodies. In this work, nAb titers were assessed as correlates of protection against COVID-19 in the casirivimab + imdevimab monoclonal antibody (mAb) prevention trial (ClinicalTrials.gov #NCT4452318) and in the mRNA-1273 vaccine trial (ClinicalTrials.gov #NCT04470427). In the mAb trial, protective efficacy of 92% (95% confidence interval (CI): 84%, 98%) is associated with a nAb titer of 1000 IU50/ml, with lower efficacy at lower nAb titers. In the vaccine trial, protective efficacies of 93% [95% CI: 91%, 95%] and 97% (95% CI: 95%, 98%) are associated with nAb titers of 100 and 1000 IU50/ml, respectively. These data quantitate a nAb titer correlate of protection for mAbs benchmarked alongside vaccine induced nAb titers and support nAb titer as a surrogate endpoint for authorizing new mAbs., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Randomized controlled trials evaluated monoclonal antibodies for the treatment (Study 2067) and prevention (Study 2069) of coronavirus disease 2019 (COVID-19). Household contacts of the infected index case in Study 2067 were enrolled in Study 2069 and prospectively followed; these cohorts provided a unique opportunity to evaluate correlates of transmission, specifically viral load., Methods: This post hoc analysis was designed to identify and evaluate correlates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, adjusting for potential confounding factors related to source SARS-CoV-2 viral load and risk of SARS-CoV-2 acquisition in this population. Correlates of transmission were evaluated in potential transmission pairs (any infected household member plus susceptible household contact)., Results: In total, 943 participants were included. In multivariable regression, 2 potential correlates were determined to have a statistically significant ( P < .05) association with transmission risk. A 10-fold increase in viral load was associated with a 40% increase in odds of transmission; sharing a bedroom with the index participant was associated with a 199% increase in odds of transmission., Conclusions: In this prospective, post hoc analysis that controlled for confounders, the 2 key correlates for transmission of SARS-CoV-2 within a household are sharing a bedroom and increased viral load, consistent with increased exposure to the infected individual., Competing Interests: Potential conflicts of interest. E. R. B. reports study funding from the NIH and the Bill & Melinda Gates Foundation (BMGF), and serving on a data and safety monitoring board for Merck for which payment was received. M. P. O. and G. H. are Regeneron Pharmaceuticals employees/stockholders who report having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application; and report grants from BARDA. B. S. and K.-C. C. are Regeneron Pharmaceuticals employees/stockholders and report grants from BARDA. F. I. is a Regeneron Pharmaceuticals employee/stockholder who reports having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, and report grants from BARDA. E. F.-N. is a former Regeneron employee and current stockholder who reports having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application; and reports grants from BARDA. P. H. is a former Regeneron Pharmaceuticals employee and current stockholder and reports grants from BARDA. M. S. C. reports a relationship with the NIH for study funding, Regeneron for drug studies, and Prime Global Options for manuscript writing support; consulting fees from Aerium for a scientific advisory board and Atrea for a medical advisory board; payment for lectures from NY Course, MJH Life Sciences, Clinical Care Solutions, Virology Education, Amgen, Medscape, and UpToDate; payment for an educational panel from AstraZeneca; support for attending meetings with Krog Healthcare-GSK, GSK, and Trinity Health Sciences; and a leadership/fiduciary role for the HIV Prevention Trials Network, CoVPN, and McGill. R. V. B. reports support for conference abstract and manuscript writing from Regeneron Pharmaceuticals, and grants from the NIH and BMGF, outside this work., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19)., Methods: Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020-April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients., Results: Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log 10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was -0.69 (95% confidence interval [CI], -1.25 to -.14) log 10 copies/mL for IC patients and -0.31 (95% CI, -.42 to -.20) log 10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%)., Conclusions: IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695., Competing Interests: Potential conflicts of interest. S. S.-K., J. M., V. M. C., A. M., M. H., S. A., R. B., and B. H. are employees/stockholders of Regeneron Pharmaceuticals, and report grants from BARDA. E. M. reports payments to his institution received from the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH), National Institute of General Medical Sciences/NIH, SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc/National Cancer Institute. E. O.-O. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals, and reports grants from BARDA. M. P. O. and G. A. H. are employees/stockholders of Regeneron Pharmaceuticals and report having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application; and report grants from BARDA. A. T. H. is an employee/stockholder of Regeneron Pharmaceuticals, a former Pfizer employee and current stockholder, has a patent pending with Regeneron Pharmaceuticals, and reports grants from BARDA. F. M. M. reports payments to his institution received from Regeneron Pharmaceuticals, F2G, Gilead, Merck, Shire, Syneos, and the Bill & Melinda Gates Foundation; reports grants or contracts from Ansun, Chimerix, Cidara, Scynexis, Shire (a Takeda company), WHISCON, AlloVir, Amplyx, F2G, Gilead, and Merck; reports consulting fees from AlloVir, Amplyx, Avir, Emcure, F2G, Gilead, Janssen, Kyorin, Merck, Regeneron, ReViral, Symbio, United Medical, ADMA Biologics, Astellas, Behring, Cidara, Octapharma, Partner Therapeutics, Shionogi, Shire (a Takeda company), and Siemens Healthineers; reports payment for honoraria from Basilea, Merck, and Merck Sharp & Dohme Europe; and reports grants from BARDA. E. F.-N. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals and reports having a patent pending, which has been licensed and receiving royalties from Regeneron Pharmaceuticals, as well as a pending patent application; and reports grants from BARDA. J. D. H. is an employee/stockholder of Regeneron Pharmaceuticals and has a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals. D. M. W. was an employee of and holds stocks and shares in Regeneron Pharmaceuticals and reports having a pending patent application; and reports grants from BARDA., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD)., Methods: In this phase 1/2/3, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.0 g CAS + IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus., Results: In total, 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met in seronegative patients, the least-squares mean difference (CAS + IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log10 copies/mL (95% confidence interval [CI], -.51 to -.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS + IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2%-74.0%). No safety concerns were noted., Conclusions: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS + IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients., Clinical Trials Registration: NCT04426695., Competing Interests: Potential conflicts of interest. S. S.-K., S. A., Y. Sun, R. B., J. Mei, J. Miller, E. F.-N., C. P., V. P., Y. Z., A. M., J. D. D., Y. K., A. C., B. K., Y. Soo, A. T. D., G. P. G., L. L., N. B., and D. M. W. are employees/stockholders of Regeneron Pharmaceuticals, Inc, and report grants from Biomedical Advanced Research and Development Authority (BARDA). E. M. reports payments to his institution received from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases, NIH/National Institute of General Medical Sciences, SciClone Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Pfizer, Chemic Labs/KODA Therapeutics, Cidara, and Leidos Biomedical Research Inc/NCI. V. P. M. and J. C. W. report grants from BARDA. S. S. is an Excision BioTherapeutics employee/stockholder and former Regeneron Pharmaceuticals, Inc, employee and current stockholder, and reports grants from BARDA. L. C. is a Regeneron Pharmaceuticals, Inc employee and reports grants from BARDA. A. T. H. is a Regeneron Pharmaceuticals, Inc employee/stockholder, a former Pfizer employee and current stockholder, has a patent pending with Regeneron Pharmaceuticals, Inc and reports grants from BARDA. J. D. H., K. C. T., and G. A. H. are employees/stockholders of Regeneron Pharmaceuticals, Inc and have a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, Inc. R. H. is a former employee and current stockholder of Regeneron Pharmaceuticals, Inc, and reports grants from BARDA. N. S. and G. D. Y. are employees/stockholders of Regeneron Pharmaceuticals, Inc, and have issued patents (US Patent Nos. 10 787 501, 10 954 289, and 10 975 139) and pending patents, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals, Inc, and reports grants from BARDA. Funding to pay the Open Access publication charges for this article was provided by Regeneron Pharmaceuticals, Inc., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings., Methods: This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318., Findings: From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal p&lt;0·0001) versus placebo (prespecified analysis). During the 7-month follow-up period, protection was greatest during months 2-5, with a 100% relative risk reduction in COVID-19 (nominal p&lt;0·0001; post-hoc analysis). Efficacy waned during months 6-8 (post-hoc analysis). Seroconversion occurred in 38 (4·5%) of 841 participants in the CAS + IMD group and in 181 (21·5%) of 842 in the placebo group during the 8-month study (79·0% relative risk reduction vs placebo; nominal p&lt;0·0001). Six participants in the placebo group were hospitalised due to COVID-19 versus none who received CAS + IMD. Serious treatment-emergent adverse events (including COVID-19) were reported in 24 (1·7%) of 1439 participants receiving CAS + IMD and in 23 (1·6%) of 1428 receiving placebo. Five deaths were reported, none of which were due to COVID-19 or related to the study drugs., Interpretation: CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown., Funding: Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health., Competing Interests: Declaration of interests GAH, MPO, FI, KCT, and JDH are Regeneron Pharmaceuticals employees and stockholders who report having a patent pending (International Patent application number PCT/US2021/035556), which has been licensed and provides royalties, with Regeneron Pharmaceuticals. EF-N, NSa, PH, K-CC, BJM, JDD, AM, JP, DS, ATD, NB, and DMW are Regeneron Pharmaceuticals employees and stockholders. MSC reports a relationship with National Institute for Health for study funding and Regeneron Pharmaceuticals for drug studies and manuscript writing support, and has a leadership or fiduciary role for HIV Prevention Trials Network, COVID-29 Prevention Network, Fogart, and McGill. CBH reports support for manuscript writing from Regeneron Pharmaceuticals, salary support from University of North Carolina at Chapel Hill, activities sponsored by Gilead Sciences, and receiving honorarium for developing content for a continuing education programme with PRIME Education. MAM reports being a federal employee who, as part of the US Government through Operation Warp Speed (later transferred into the responsibilities of the White House COVID-19 Response Team), supported the clinical trial network involved in implementation of this effort. ATH is a Regeneron Pharmaceuticals employee and stockholder, a former Pfizer employee and current stockholder, and reports having a patent pending (International Patent application number PCT/US2021/035556), which has been licensed and provides royalties, with Regeneron Pharmaceuticals. AB, CAK, NSt, and GDY have issued patents (US patent number 10 787 501, 10 954 289, and 10 975 139) and pending patents (International Patent application number PCT/US2020/039707), which have been licensed and provide royalties, with Regeneron Pharmaceuticals. KJB and DRB declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: A phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) in uninfected adult volunteers., Methods: Participants were randomized (3:1) to SC CAS+IMD 1200 mg or placebo every 4 weeks for up to six doses. Primary and secondary end points evaluated safety, pharmacokinetics, and immunogenicity. Exploratory efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion., Results: In total, 969 participants received CAS+IMD. Repeat monthly dosing of SC CAS+IMD led to a 92.4% relative risk reduction in clinically defined COVID-19 compared with placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio 0.07 [95% CI 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies occurred in a small proportion of participants (<5%). No grade ≥3 injection-site reactions (ISRs) or hypersensitivity reactions were reported. Slightly more participants reported treatment-emergent adverse events with CAS+IMD (54.9%) than with placebo (48.3%), a finding that was due to grade 1-2 ISRs. Serious adverse events were rare. No deaths were reported in the 6-month treatment period., Conclusion: Repeat monthly administration of 1200 mg SC CAS+IMD was well-tolerated, demonstrated low immunogenicity, and showed a substantial risk reduction in COVID-19 occurrence., Competing Interests: Declarations of competing interest FI, MPO, KCT, SG, JDH, and GAH are Regeneron employees/stockholders and have a patent pending, which has been licensed and receiving royalties, with Regeneron. EF-N, JM, WZ, LF, NS, BJM, SB, AM, AD, YK, BK, YS, GPG, LL, NB, and DMW are Regeneron employees/stockholders. CB reports grants or contracts from Gilead, Lilly, and GlaxoSmithKline for clinical trials. IH is a Regeneron consultant and Merck & Co. stockholder. ATH is a Regeneron employee/stockholder and former Pfizer employee and current stockholder. GDY is a Regeneron employee/stockholder and has issued patents (US Patent Nos. 10,787,501, 10,954,289, and 10,975,139) and pending patents, which have been licensed and receiving royalties, with Regeneron. SR, DA, MO, and SF have no conflicts to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: The monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients., Objective: To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo., Design, Setting, and Participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021., Interventions: Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo., Main Outcomes and Measures: The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline., Results: Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1 (10.0) years (102 [45.3%] men; 75 [34.7%] Hispanic or Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusion-related or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported., Conclusions and Relevance: In this randomized clinical trial including outpatients with asymptomatic and low-risk symptomatic SARS-CoV-2, all IV and SC doses of casirivimab and imdevimab comparably reduced viral load., Trial Registration: ClinicalTrials.gov Identifier: NCT04666441.

Importance: Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage., Objective: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19., Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported., Interventions: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156)., Main Outcomes and Measures: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL)., Results: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19., Conclusions and Relevance: Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days., Trial Registration: ClinicalTrials.gov Identifier: NCT04452318.

Background: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI)., Methods: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI)., Results: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups., Conclusions: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts., Clinical Trials Registration: NCT02325791., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

We describe outcomes from the first-in-human study of garetosmab (a fully human monoclonal antibody that inhibits activin A) under development for the treatment of fibrodysplasia ossificans progressiva (FOP). In a double-blind, placebo-controlled phase 1 study, 40 healthy women of nonchildbearing potential were randomized to receive a single dose of intravenous garetosmab 0.3, 1, 3, or 10 mg/kg; subcutaneous garetosmab 300 mg; or placebo. Serum concentrations of functional garetosmab (with ≥1 arm free to bind to target), total activin A, and antidrug antibodies were measured predose and up to 113 days post-first dose. Garetosmab demonstrated an acceptable safety profile with no dose-limiting toxicities. Garetosmab displayed nonlinear pharmacokinetics with target-mediated elimination. With increasing doses of intravenous garetosmab, mean peak concentration increased in a dose-proportional manner; mean steady-state estimates ranged from 41.4 to 47.8 mL/kg. A greater than dose-proportional increase in mean area under the concentration-time curve from time zero extrapolated to infinity (range, 72.2-7520 mg*day/L) was observed, consistent with decreasing mean clearance (range, 4.35-1.34 mL/day/kg). Following administration of intravenous garetosmab, mean concentrations of total activin A increased in a dose-dependent manner. At 10 mg/kg, total activin A levels reached a state of little or no change between weeks 4 and 12, suggesting saturation of the target-mediated pathway. No safety signals were seen in this study to preclude investigation in patients. Following intravenous administration, garetosmab concentrations decreased quickly, then decreased over time (reflecting linear elimination), and finally decreased in a nonlinear phase, reflecting target-mediated elimination. Results here support further investigation. Garetosmab 10 mg/kg every 4 weeks intravenously is being evaluated in patients with FOP (NCT03188666)., (© 2020 Regeneron Pharmaceuticals, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Quadrivalent influenza vaccines (QIVs), which include both B lineage strains, are expected to provide broader protection than trivalent influenza vaccines (TIVs). The non-inferiority, immunogenicity, and safety of a cell culture-based investigational QIVc and 2 TIVs (TIV1c, TIV2c), in adults (≥18 y), were evaluated in this Phase III, double-blind, multicenter study. A total of 2680 age-stratified subjects were randomized (2:1:1) to receive 1 dose of QIVc (n = 1335), TIV1c (n = 676), or TIV2c (n = 669). TIV1c (B/Yamagata) and TIV2c (B/Victoria) differed only in B strain lineage. The primary objective was to demonstrate non-inferiority of the hemagglutinin-inhibition antibody responses of QIVc against TIVc, 22 d post-vaccination. Secondary objectives included the evaluation of immunogenicity of QIVc and TIVc in younger (≥18 - <65 y) and older (≥65 y) adults. Hemagglutinin inhibition assays were performed at days 1 and 22. Solicited local and systemic adverse events (AEs) were monitored for 7 d post-vaccination, and unsolicited AEs and serious AEs until day 181. QIVc met the non-inferiority criteria for all 4 vaccine strains and demonstrated superiority for both influenza B strains over the unmatched B strain included in the TIV1c and TIV2c, when geometric mean titers and seroconversion rates with TIVc were compared at day 22. Between 48%-52% of subjects experienced ≥1 solicited AE, the most common being injection-site pain and headache. Serious AEs were reported by ≤1% of subjects, none were vaccine-related. The results indicate that QIVc is immunogenic and well tolerated in both younger and older adults. The immunogenicity and safety profiles of QIVc and TIVc were comparable at all ages evaluated.

Background: We compared the immunogenicity, safety and 1-year antibody persistence of a single-dose and a 2-dose series of a licensed meningococcal ACWY-CRM conjugate vaccine (MenACWY-CRM) in 2- to 10-year-old children., Methods: In this phase III, multicenter, observer-blind study, children aged 2-5 years (n = 359) and 6-10 years (n = 356) were randomized 1:1 to receive 2 doses of MenACWY-CRM (ACWY2) or 1 dose of placebo followed by 1 dose of MenACWY-CRM (ACWY1), 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement (hSBA). Primary outcomes were to assess the immunologic noninferiority and superiority of ACWY2 versus ACWY1., Results: One-month after the second dose, the hSBA seroresponse in ACWY2 was noninferior to ACWY1 for all 4 serogroups, in both age cohorts, and was superior for serogroups C and Y in the 2- to 5-year-old age cohort and for serogroup Y in the 6- to 10-year-old age cohort. Overall, 90%-99% of subjects in ACWY2 and 65%-96% in ACWY1 had hSBA titers ≥ 8; geometric mean titers were 1.8- to 6.4-fold higher in ACWY2 than ACWY1 across serogroups. At 1 year postvaccination, geometric mean titers declined, and the differences between ACWY2 and ACWY1 remained significant for serogroups A and C in the 2- to 5-year-old age cohort and for serogroups C and Y in the 6- to 10-year-old age cohort. The safety profile of MenACWY-CRM was similar in both groups., Conclusions: The single dose and 2-dose MenACWY-CRM series were immunogenic and well tolerated. Although antibody responses were greater after 2 doses, especially in the 2- to 5-year-old age cohort, this difference was less pronounced at 1 year postvaccination.

Objectives: The safety and immunogenicity of mammalian cell-derived quadrivalent influenza vaccine (QIVc) as compared with trivalent influenza vaccines (TIV1c/TIV2c) was evaluated in children aged ≥4 to <18 years., Methods: Two thousand three hundred and thirty-three subjects were randomized 2:1:1 to receive either one or two doses of study vaccine depending on previous vaccination status. Hemagglutination inhibition antibody responses for all four influenza strains were performed 3 weeks after the last dose. Reactogenicity and safety were also assessed (ClinicalTrials.gov: NCT01992107)., Results: QIVc met the non-inferiority criteria against all four vaccine strains and demonstrated superiority for both influenza B strains over the unmatched B lineage included in the comparator vaccines, when geometric mean titers and seroconversion rates were compared at 3 weeks after the last vaccination. Similar percentages of subjects experienced solicited and unsolicited adverse events (AEs) across all subgroups. Unsolicited AEs, serious AEs, medically attended AEs, and new onset chronic disease were reported in comparable percentages of subjects in all study groups. No vaccine-related serious AEs or deaths occurred., Conclusions: QIVc demonstrated a similar safety profile and immunogenicity responses against all four vaccine strains without signs of immune interference on addition of an alternate lineage B strain compared with TIV1c/TIV2c and may provide broader protection against both influenza B lineages in children., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This phase 3b randomized, open-label study evaluated the immunogenicity and safety of coadministration of a hepatitis A and/or B vaccine with a quadrivalent oligosaccharide meningococcal CRM197 -conjugate vaccine (MenACWY-CRM), in the context of an accelerated hepatitis A and/or B immunization schedule., Methods: A total of 252 healthy adult subjects were randomized to three groups to receive hepatitis A/B only (HepA/B), hepatitis A/B coadministered with MenACWY-CRM (HepA/B+MenACWY-CRM), or MenACWY-CRM only (MenACWY-CRM). Hepatitis A and/or B vaccination was administered in the form of a single booster dose or a primary three-dose series, depending on the hepatitis A and/or B vaccination history of subjects. Antibody responses to hepatitis A/B vaccination were assessed 1 month following the last hepatitis A and/or B dose. Serum bactericidal activity with human complement (hSBA) against meningococcal serogroups A, C, W-135, and Y was assessed 1 month post-MenACWY-CRM vaccination. Safety was monitored throughout the study., Results: At 1 month following the final hepatitis A and/or B vaccination, concomitant administration of hepatitis A/B and MenACWY-CRM was non-inferior to administration of hepatitis A/B alone in terms of geometric mean concentrations of antibodies against the hepatitis A and B antigens. One month post-MenACWY-CRM vaccination, the percentages of subjects achieving hSBA titers ≥8 for serogroups A, C, W-135, and Y in the HepA/B+MenACWY-CRM group (76, 87, 99, and 94%, respectively) were comparable to those in the MenACWY-CRM group (67, 82, 96, and 88%, respectively). The percentages of subjects reporting adverse events (AEs) were similar across study groups and a majority of the reported AEs were mild to moderate in nature. There were no study vaccine-related serious AEs., Conclusions: MenACWY-CRM can be administered concomitantly with a hepatitis A and/or B vaccine in the context of an accelerated hepatitis A and/or B immunization schedule without increasing safety concerns or compromising the immune responses to any of the vaccine antigens. [NCT01453348]., (© 2014 International Society of Travel Medicine.)

Background: Compact and short pre-travel immunization schedules, which include several vaccinations in a single visit, are desirable for many travelers. However, concomitant vaccination could potentially compromise immunogenicity and/or safety of the individual vaccines and, therefore, possible vaccine interferences should be carefully assessed. This article discusses the immunogenicity and safety of travel vaccines for typhoid fever (TF) and yellow fever (YF), when administered with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine (MenACWY-CRM)., Methods: Healthy adults (18-≤60 years) were randomized to one of three vaccine regimens: TF + YF + MenACWY-CRM (group I; n = 100), TF + YF (group II; n = 101), or MenACWY-CRM (group III; n = 100). Immunogenicity at baseline and 4 weeks post-vaccination (day 29) was assessed by serum bactericidal assay using human complement (hSBA), enzyme-linked immunosorbent assay (ELISA), or a neutralization test. Adverse events (AEs) and serious adverse events (SAEs) were collected throughout the study period., Results: Non-inferiority of post-vaccination geometric mean concentrations (GMCs) and geometric mean titers (GMTs) was established for TF and YF vaccines, respectively, when given concomitantly with MenACWY-CRM vaccine versus when given alone. The percentages of subjects with seroprotective neutralizing titers against YF on day 29 were similar in groups I and II. The antibody responses to meningococcal serogroups A, C, W-135, and Y were within the same range when MenACWY-CRM was given separately or together with TF and YF vaccines. The percentage of subjects reporting AEs was the same for TF and YF vaccines with or without MenACWY-CRM vaccine. There were no reports of SAEs or AEs leading to study withdrawals., Conclusions: These data provide evidence that MenACWY-CRM can be administered with typhoid Vi polysaccharide vaccine and live attenuated YF vaccine without compromising antibody responses stimulated by the individual vaccines. MenACWY-CRM can, therefore, be incorporated into travelers' vaccination programs without necessitating an additional clinic visit (NCT01466387)., (© 2014 International Society of Travel Medicine.)

Introduction: Annual seasonal influenza epidemics are particularly dangerous for the very young, the elderly and chronically ill individuals, in whom infection can cause severe morbidity, hospitalization and death. Existing, nonadjuvanted influenza vaccines exhibit a suboptimal immunogenicity and efficacy in immunologically naive subjects such as young children., Methods: This phase II, randomized clinical trial was conducted to evaluate the antibody and cell-mediated responses to a trivalent influenza vaccine administered without adjuvant (TIV) or adjuvanted with MF59 (ATIV) in previously nonvaccinated children less than 3 years of age., Results: The MF59-adjuvanted vaccine was well tolerated, and induced higher titers of hemagglutination inhibition antibodies able to recognize strains different from the one used in the vaccine (heterovariant) than TIV. The presence of the adjuvant MF59 induced a larger expansion of vaccine-specific CD4 T cells. Interestingly, the adjuvant MF59 did not modify the cytokine profile of the elicited T cells, characterized by the production of IL-2 and TNF-α, and did not bias the response toward either Th1 or Th2. The advantage of ATIV over TIV was more pronounced for the virus strains that had not circulated in the years that preceded this study and for the heterovariant strains., Conclusion: These data highlight the relevant role played by the oil-in-water adjuvant MF59 in enhancing the immunogenicity of inactivated influenza vaccines in immunologically naive individuals.

Background: Non-adjuvanted seasonal influenza vaccines show only modest efficacy in young children. This study compared the immunogenicity, reactogenicity and safety of the MF59-adjuvanted trivalent subunit vaccine (aTIV) with two non-adjuvanted trivalent vaccines, TIV-1, the non-adjuvanted version of aTIV, and TIV-2, a split virion vaccine., Methods: 6078 children received two doses of aTIV (n=3125), TIV-1 (n=1479), or TIV-2 (n=1474) four weeks apart (Days 1 and 29). Children aged 6 to <36 months and 36 to <72 months received 0.25 mL and 0.50 mL doses, respectively. Immunogenicity was assessed by hemagglutination inhibition (HI) assay (n=2435) on Days 1, 29, 50 and 209. Safety was assessed up to Day 394., Results: After the second vaccination (Day 50), the aTIV group showed significantly higher geometric mean HI titers and seroconversion rates than the TIV-1 or TIV-2 groups against all homologous and heterologous strains. The difference was enhanced at HI titers ≥110. aTIV elicited a faster, more persistent antibody response, with significantly higher titers in the aTIV group after one vaccination (Day 29) and after six months (Day 209) than in either TIV group. aTIV was more reactogenic than were TIV-1 and TIV-2 but rates of severe adverse events were very low for all three vaccines., Conclusion: In infants and young children, the MF59-adjuvanted vaccine induced substantially faster (after one dose), higher, persistent HI titers than the non-adjuvanted vaccines, with consistently higher seroprotection rates at increased threshold HI titers. This trial is registered at clinicaltrials.gov: NCT01346592., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aim: Adjuvanted influenza vaccines can overcome the poor antibody response of conventional non-adjuvanted vaccines in the elderly. We evaluated the immunogenicity, safety and clinical effectiveness of an MF59(®)-adjuvanted trivalent influenza vaccine (aTIV) compared with a non-adjuvanted vaccine (TIV) in subjects ≥65 years old, with or without co-morbidities., Methods: In 2010-2011, subjects (N=7082) were randomized to receive one dose of aTIV or TIV. Co-primary objectives were to assess lot-to-lot consistency of aTIV, non-inferiority, superiority and immunogenicity 22 days after vaccination. Clinical effectiveness, reactogenicity and serious adverse events were monitored up to Day 366., Results: The immunological equivalence of three lots of aTIV was demonstrated. aTIV was not only non-inferior to TIV but also elicited significantly higher antibody responses at Day 22 than TIV against all homologous and heterologous strains, even in subjects with co-morbidities. Superiority was not established. Reactogenicity was higher in the aTIV group, but reactions were mild to moderate and transient., Conclusions: aTIV elicited a significantly higher antibody response than TIV, especially against A/H3N2 strains, although superiority by pre-defined criteria was not formally met. The study demonstrates potential immunological benefits of MF59-adjuvanted influenza vaccines for the elderly. This trial was registered with www.clinicaltrials.gov (NCT01162122)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Potential interactions between vaccines may compromise the immunogenicity and/or safety of individual vaccines so must be assessed before concomitant administration is recommended. In this study, the immunogenicity and safety of travel vaccines against Japanese encephalitis (JEV) and rabies (PCECV) administered together with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine were evaluated (NCT01466387)., Method: Healthy adults aged 18 to ≤60 years were randomized to one of four vaccine regimens: JEV + PCECV + MenACWY-CRM, JEV + PCECV, PCECV or MenACWY-CRM. Immunogenicity at baseline and 28 days post-complete vaccination was assessed by serum bactericidal assay using human complement or neutralization tests. Adverse events (AEs) were collected throughout the study period., Results: JEV + PCECV + MenACWY-CRM was non-inferior to JEV + PCECV. Post-vaccination seroprotective neutralizing titers or concentrations were achieved in 98-99% (JE) and 100% (rabies) of subjects across the vaccine groups. Antibody responses to vaccine meningococcal serogroups were in the same range for MenACWY-CRM and JEV + PCECV + MenACWY-CRM. Rates of reporting of AEs were similar for JEV + PCECV and JEV + PCECV + MenACWY-CRM., Conclusions: MenACWY-CRM was administered with an inactivated adjuvanted JE and a purified chick embryo cell-culture rabies vaccine without compromising immunogenicity or safety of the individual vaccines. These data provide evidence that MenACWY-CRM could be effectively incorporated into travel vaccination programs., Trial Number: NCT01466387., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Human metapneumovirus (HMPV) is a member of the subfamily Pneumovirinae within the family Paramyxo- viridae. Other members of this subfamily, respiratory syncytial virus and avian pneumovirus, can be divided into subgroups on the basis of genetic or antigenic differences or both. For HMPV, the existence of different genetic lineages has been described on the basis of variation in a limited set of available sequences. We address the antigenic relationship between genetic lineages in virus neutralization assays. In addition, we analyzed the genetic diversity of HMPV by phylogenetic analysis of sequences obtained for part of the fusion protein (n = 84) and the complete attachment protein open reading frames (n = 35). On the basis of sequence diversity between attachment protein genes and the differences in virus neutralization titers, two HMPV serotypes were defined. Each serotype could be divided into two genetic lineages, but these did not reflect major antigenic differences.

Background: Approximately 10% of the general population worldwide acquires influenza infection every year. Airline crews run a particularly high risk of contracting influenza and influenza-like viruses because they come in contact with hundreds of potentially infected individuals every day. Respiratory diseases are the most frequent cause of absenteeism among flight crews in airline companies. Several studies have shown the efficacy of influenza vaccination in the workplace of healthy, working adults leading to increased productivity and lower absenteeism. We conducted a double blind, randomized, placebo-controlled study on flight crews of an airline company in order to determine the safety and efficacy of a trivalent inactivated influenza vaccine in reducing illness and absences from work., Methods: The 813 healthy members of a Brazilian airline company were randomly assigned to receive injections of either an influenza vaccine or a placebo, with a follow-up period of 7 mo after vaccination. Primary outcomes included influenza-like illness episodes and absenteeism from work due to such episodes., Results: Demographic characteristics were similar in the two groups. No significant side-effects occurred in either group. Compared to the placebo group, individuals receiving the vaccine showed 39.5% fewer episodes of flu-like illness (p < 0.001) and 26% fewer days of work lost (p = 0.03). The vaccinated group developed 33% fewer episodes of any severe flu-like illness (p < 0.01)., Conclusion: The data indicates that influenza vaccination is safe in airline flight crews and may produce health-related benefits including reduced absenteeism.

This study investigated the immunogenicity and safety of including a Haemophilus influenzae type b vaccine (polyribosylribitol phosphate conjugated to tetanus toxoid, PRP-T) in three different vaccination schemes: (1) PRP-T reconstituted with a combined diphtheria-tetanus-pertussis-inactivated poliovirus vaccine (DTP-IPV//PRP-T); (2) PRP-T reconstituted with DTP and administered concomitantly with an oral poliovirus vaccine (DTP//PRP-T+OPV); and (3) PRP-T administered concomitantly with DTP at a different injection site and OPV (DTP+PRP-T+OPV). Vaccines were given at 2, 4, and 6 months of age. A total of 252 infants were enrolled, and randomly assigned to one of the three vaccination groups (84 infants in each group); 241 infants were followed until the end of the study. Antibody production against PRP, diphtheria, tetanus and pertussis antigens was satisfactory for each vaccination scheme used. A good response to Hib vaccine was elicited in each group, and 3 months after the third vaccine dose, at least 97% of children in each group had levels of PRP antibody considered to be seroprotective (>0.15 microg/ml), and over 90% of children in each group had levels over 1. 0 microg/ml. The solicited local and systemic adverse events following vaccination were mild in all groups and resolved within 4 days without medical intervention. With the exception of fever, which was more common after the second dose in children who received DTP-IPV//PRP-T, local and systemic reactions did not differ between the vaccination groups. Due to the practical advantages of combined vaccines, their use in routine immunization programs in developing countries is highly desirable. Our results show that Hib conjugate vaccine can be included in routine immunization programs that include either OPV or IPV with satisfactory immunogenicity and safety profiles. This flexible approach should facilitate the inclusion of the Hib conjugate vaccine in routine immunization programs on a world-wide scale.

The serological response to MMR vaccine was evaluated in 109 9-month-old infants having no history of measles vaccination, and in 98 15-month-old children who had received monocomponent measles immunisation at 9 months. The combined vaccine contained Schwarz, Urabe Am9, and Wistar RA 27/3 live attenuated virus strains. Preimmunisation antibody levels were extremely low for the 9-month-old children, indicating that maternally-transmitted antibodies do not persist at this age. In the case of mumps, preimmunisation antibody levels were significantly higher in the 15-month-old than in the 9-month-old group. A difference between groups in terms of postimmunisation antibody titres was observed only for rubella, with titres being significantly higher in the older group. Seroconversion rates were high in both groups and no serious events attributable to vaccination were observed. The MMR vaccine can thus be administered to children as young as 9 months of age. Evidence for the efficacy of a two-dose schedule, i.e. at 9 and 15 months, is presented.